1. Field of the Invention
This invention relates to certain novel fused quinazoline derivatives as tyrosine kinase inhibitors, their synthesis and their use for treating a tyrosine kinase mediated disorder. More particularly, this invention is directed to fused quinazoline derivatives useful as inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase or vascular endothelial growth factor receptor (VEGFR) tyrosine kinase, methods for producing such compounds and methods for treating a EGFR or VEGFR tyrosine kinase-mediated disorder.
2. Brief Description of the Related Art
Receptor tyrosine kinases are transmembrane proteins involved in signal transduction. They propagate growth factor signals from the cell surface to intracellular processes that control critical functions such as growth, differentiation, angiogenesis and inhibition of apoptosis. In malignancies, these signaling pathways are often exploited to optimize tumor growth and metastasis. One such family of receptor tyrosine kinases is the epidermal growth factor receptor (EGFR) tyrosine kinase. These receptors are overexpressed in a wide variety of major human cancers such as brain, lung, squamous cell, bladder, gastric, breast, head and neck, oesophageal, gynecological and thyroid cancers. Another family of receptor tyrosine kinases is the vascular endothelial growth factor (VEGF) receptor tyrosine kinase. VEGF is an important stimulator of both normal and pathological angiogenesis which has been associated with many cancers and other disorders. Thus, an inhibitor of EGFR or VEGF receptor tyrosine kinase, is useful for treating a variety of human cancers.
U.S. Pat. No. 5,616,582 discloses quinazoline derivatives of the formula below as EGFR inhibitors:
wherein m is 1, 2 or 3 and each R1 includes hydroxy, amino, carboxy, carbamoyl, ureido, (1–4C)alkoxycarbonyl, N(1–4C)alkylcarbamoyi, N,N-di[(1–4C)alkyl]carbamoyl, hydroxyamino, (1–4C)alkylamino, (2–4C)alkanoyloxyamino, trifluoromethoxy, (1–4C)alkyl, (1–4C)alkoxy and (1–3C)alkenedioxy; n is 1 or 2 and each R2 includes; hydrogen, hydroxy, halogeno, trifluoromethyl, amino, nitro, cyano and (1–4C)alkyl.
U.S. Pat. No. 5,569,658 discloses tricyclic derivatives of the formula below as EGFR inhibitors:
wherein R1 and R2 together form specified optionally substituted groups containing at least one heteroatom so as to form a 5 or 6 membered ring, and R3 includes independently hydrogen, hydroxy, halogeno, (1–4C)alkyl, (1–4C)alkoxy, di-[(1–4C)alky[amino, or (2–4C)alkanoylamino.
WO 95/19970 discloses tricyclic derivatives of the formula below as EGFR inhibitors:
wherein: 1) Y and Z are both C, both N or one N and the other C, in which case the ring structure is a linearly fused 6,6 (5 or 6) tricycle, or 2) one of Y and Z is C═C, C═N, whereupon the other one of Y or Z is simply a bond between the two aromatic rings, then the ring structure is a nonlinear 6,6 (5 or 6) tricycle, or 3) one of Y and Z is N, O or S, whereupon the other one of Y or Z is simply a bond between the two aromatic rings, then the ring structure is a fused 6,5 (5 or 6) tricycle; A, B, D and E can all be carbon, or up to two of them can be nitrogen, whereupon the remaining atoms must be carbon, or any two contiguous positions in A–E can be a single heteroatom, N, O or S, forming a five membered fused ring, in which case one of the two remaining atoms must be carbon, and the other can be either carbon or nitrogen, except that the case where A and B taken together, and D and E taken separately are all three nitrogen atoms; X═O, S, NH or NR9, such that R9=lower alkyl (1–4 carbon atoms) , OH, NH2, lower alkoxy (1–4 carbon atoms) or lower monoalkylamino (1–4 carbon atoms); R1=H or lower alkyl; n=0, 1 or 2; Ar is aryl and heteroaryl.
WO 97/13760 discloses tricyclic derivatives of the formula below as EGFR inhibitors:
wherein J, K, L and M form a saturated or unsaturated fused ring which is optionally substituted and in which: (i) each of J, K, L and M represent carbon atoms that may be independently replaced by N, O or S; or (ii) any two contiguous positions in J, K, L and M taken together represent a single atom C, N, O or S with at least one of the remaining atoms being carbon and the other being selected from carbon, N, O or S; or (iii) any two contiguous positions in J, K, L and M taken together represent a N atom with the remaining atoms also being N; so that when the fused 5 or 6-membered ring represented by J, K, L and M bears one or two optional substituents in order to satisfy the valency requirements of the atoms in the fused ring and: (i) when the ring atom is carbon, the substituents are independently selected from the group comprising: amino, cyano, halogen, hydroxy, C1–4 alkyl, C1–4 alkoxy, C14 4 alkylthio, C1–4 alkylsulphinyl, C1-4 alkylamino, or (ii) when there are two adjacent carbon atoms in the fused ring, two substituents together form an optionally substituted methylenedioxy or ethylenedioxy group, or (iii) when the ring atom is nitrogen, the substituents are independently selected from the group comprising: C1–4 alkyl, amino C2–4 alkyl, hydroxy C2–4 alkyl and C1–4 alkoxy C2–4 alkyl; subject to the provisos in (i) and (ii) above that the skeleton of the fused heterocyclic ring does not contain more than two atoms selected from O and S, and where the fused ring contains two such atoms said atoms do not occupy adjacent positions in the fused ring; P and O are carbon atoms in an aromatic ring which may be independently replaced to form an aromatic or non-aromatic ring by O, N, S, or a bond; or one of P and Q is C═C or C═N and the other a bond; X is N or CH; Y is a group W(CH2), (CH2)W, or W, in which W is O, S(O)m wherein m is 0, 1 or 2, or NRa wherein Ra is hydrogen or a C1–8 alkyl group.
U.S. Pat. No. 5,747,498 discloses quinazoline derivatives of the formula below as EGFR inhibitors:
wherein: m is 1, 2, or 3; each R1 is independently selected from the group consisting of hydrogen, halo, hydroxy, hydroxyamino, carboxy, nitro, guanidino, ureido, cyano, trifluoromethyl, and —(C1–C4 alkylene)-W— (phenyl) wherein W is a single bond, O, S or NH; or each R1 is independently selected from R9 and C1–C4 alkyl substituted by cyano, wherein R9 is selected from the group consisting of R5, —OR6, —NR6R6, —C(O)R7, —NHOR5, —OC(O)R6, cyano, A and —YR5; R5 is C1–C4 alkyl; R6 is independently hydrogen or R5; R7 is R5, —OR6 or —NR6R6; A is selected from piperidino, morpholino, pyrrolidino, 4-R6-piperazin-1-yl, imidazol-1-yl, 4-pyridon-1-yl, —(C1–C4 alkylene)(CO2H), phenoxy, phenyl, phenylsulfanyl, C2–C4alkenyl, and —(C1–C4 alkylene)C(O)NR6R6; and Y is S, SO, or SO2; wherein the alkyl moieties in R5, —OR6 and —NR6R6 are optionally substituted by one to three halo substituents and the alkyl moieties in R5, —OR6 and —NR6R6 are optionally substituted by 1 or 2 R9 groups, and wherein the alkyl moieties of said optional substituents are optionally substituted by halo or R9, with the proviso that two heteroatoms are not attached to the same carbon atom; or each R1 is independently selected from —NHSO2R5, phthalimido-(C1–C4)-alkylsulfonylamino, benzamido, benzenesulfonylamino, 3-phenylureido, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, and R10—(C2–C4)-alkanoylamino wherein R10 is selected from halo, —OR6, C2–C4 alkanoyloxy, —C(O)R7, and —NR6R6; and wherein said —NHSO2R5, phthalimido-(C1–C4-alkylsulfonylamino, benzamido, benzenesulfonylamino, 3-phenylureido, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, and R10—(C2–C4)-alkanoylamino R1 groups are optionally substituted by 1 or 2 substituents independently selected from halo, C1–C4alkyl, cyano, methanesulfonyl and C1–C4 alkoxy; or two R1 groups are taken together with the carbons to which they are attached to form a 5–8 membered ring that includes 1 or 2 heteroatoms selected from O, S and N; R2 is hydrogen or C1–C6 alkyl optionally substituted by 1 to 3 substituents independently selected from halo, C1–C4 alkoxy, —NR6R6, and —NHSO2R5; n is 1 or 2 and each R3 is independently selected from hydrogen, halo, hydroxy, C1–C6 alkyl, —NR6R6, and C1–C4 alkoxy, wherein the alkyl moieties of said R3 groups are optionally substituted by 1 to 3 substituents independently selected from halo, C1–C4 alkoxy, —NR6R6, and —NHSO2R5; and, R4 is azido or —(ethynyl)-R11 wherein R11 is hydrogen or C1–C6 alkyl optionally substituted by hydroxy, —OR6, or —NR6R6.
WO 97/49688 discloses tricyclic derivatives of the formula below as EGFR inhibitors:
wherein: n is 0 to 2; R1 is hydrogen or C1–C6 alkyl optionally substituted by 1 to 3 substituents independently selected from the group consisting of halo, C1–C4 alkoxy, —NR6R7, and —SO2R5; each R2 is independently selected from the group consisting of halo, hydroxy, C1–C6 alkyl, —NR6 R7, and C1–C4 alkoxy, wherein said alkyl group and the alkyl moieties of said R2 groups are optionally substituted by 1 to 3 substituents independently selected from the group consisting of halo, C1–C4 alkoxy, —NR6R7 and —SO2R5; R3 is azido or —(ethynyl)-R8 wherein R8 is hydrogen or C1–C6 alkyl optionally substituted by hydroxy, —OR6, or —NR6R7; R4 is H, C1–C4 alkyl, (C1–C4 alkoxy)C1–C4 alkyl, C1–C4 alkanoyl, C1–C4 alkoxy or —S(O)x(C1–C4 alkyl) wherein x is 0 to 2, and wherein said alkyl group and the alkyl moieties of said R4 groups are optionally substituted by 1 to 3 halogens; each R5 is C1–C4 alkyl optionally substituted by 1 to 3 halogens; R6 and R7 are independently selected from hydrogen and R5; and, Z is a 5 to 8 membered fused ring that includes 0 to 3 heteroatoms selected from O, S and N.